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Biology‐Oriented Synthesis of a Withanolide‐Inspired Compound Collection Reveals Novel Modulators of Hedgehog Signaling
Author(s) -
Švenda Jakub,
Sheremet Michael,
Kremer Lea,
Maier Lukáš,
Bauer Jonathan O.,
Strohmann Carsten,
Ziegler Slava,
Kumar Kamal,
Waldmann Herbert
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201500112
Subject(s) - natural product , hedgehog signaling pathway , hedgehog , biology , smoothened , computational biology , in silico , signal transduction , structural motif , withanolide , biochemistry , chemistry , stereochemistry , withania somnifera , gene , medicine , alternative medicine , pathology
Biology‐oriented synthesis employs the structural information encoded in complex natural products to guide the synthesis of compound collections enriched in bioactivity. The trans ‐hydrindane dehydro‐δ‐lactone motif defines the characteristic scaffold of the steroid‐like withanolides, a plant‐derived natural product class with a diverse pattern of bioactivity. A withanolide‐inspired compound collection was synthesized by making use of three key intermediates that contain this characteristic framework derivatized with different reactive functional groups. Biological evaluation of the compound collection in cell‐based assays that monitored biological signal‐transduction processes revealed a novel class of Hedgehog signaling inhibitors that target the protein Smoothened.